Testosterone and aging

Aging

Aging refers to the deterioration of biological functions, over time, that are necessary for survival and fertility. As men age, there are telltale signs of the aging process. After they get into their 30s, commonly observed changes relate to:

The skin starts to wrinkle, muscle mass and strength reduce, vital body functions erode, and quality of life suffers. The most common worries men report in their body about aging include:

Lower Strength

Frailty and disability

Sexual dysfunction

Cognitive dysfunction

Reduced vitality, well-being, and quality of life

Prostate enlargement

Cardiovascular health (heart functioning) concerns

Others (lower priority) e.g., fractures

Research in the aging process is in early stage, however, there are two schools of thoughts. The first one believes aging is part of the natural selection process: once the animal (e.g., salmon) has reproduced and raised the offspring, it can die. The second school of thought believes in a genetic component that can be altered to slow down the aging process.

Considering the slow decline in daily functions, it is natural that people look for possible signs and triggers that can be monitored and acted upon to counter the aging process. Many believe one such sign is the testosterone levels in men.

As the total testosterone versus age plot above shows, the levels continuously drop with age after 30s. Terms such as adrenopause, somatopause, and andropause have been used to describe the gradual decline of hormones, such as DHEA (dehydroepiandrosterone), DHEAS (DHEA-sulfate), and GH (growth hormone). However, this declining behavior is true for many other physiological processes in the body.

The next obvious question will be the relationship between age and hormones. Is aging caused by these low levels? Or, are they simply a symptom of this process?

Data collected for those supplementing their levels from low testosterone treatment suggest some of these symptoms of aging can be improved, however, that’s not always true and can not be generalized. The research in this field has not conclusively confirmed improvement in symptoms for everyone, however, those with artificially low testosterone levels seem to benefit the most.

Many home based low testosterone level tests are becoming popular, however, one should understand the available scientific knowledge in order to the most benefit out of them.

This research based article looks at several testosterone studies and tries to answer a few basic questions around the how testosterone levels change throughout a men’s life span, the age related challenges in testosterone measurements, the guidelines from FDA, and the future opportunities for researchers and medical providers.

A brief history of testosterone

Historically, men considered testosterone as the ‘youth’ hormone. Over hundred years ago, at the time of almost no medical regulation, several people claimed unbelievable health benefits by using testosterone (via self-injections with animal samples).

However, this started to change around WWII when Ruzicka and Butenandt independently isolated and synthesized testosterone. Both received the Nobel prize for their achievements in 1939.

Soon, research in this field exploded and first medical product for human use became available in 1950s. However, an oral pill never successfully commercialized since testosterone is weakly soluble in water and difficult to absorb. And the liver rapidly digests it resulting in liver damage.

Therefore, focus has shifted to other forms: gels, skin patches, injections, nasal sprays, or gum patches. However, none of them have so far delivered a product that is safe, effective, inexpensive, easy to use, non-irritant, has minimal side-effects, and can deliver doses for prolonged periods.

Due to the ever increasing interest in testosterone, in 1992, the FDA, NIH, and WHO decided to postulate guidelines for a testosterone patch that could be safely used for those with clinically low levels. However, the patches were found to be skin irritant and a better solution was required.

Injections of testosterone in oil suspension were also approved but levels fluctuate significantly from beginning till end. The inconvenience of self-injection or doctor visits limited their adoption. In 2000, first testosterone gels appeared in the market. These could be easily utilized, however, the constant worry of affecting those coming in contact still remained a problem.

In 2014, the first FDA approved nasal spray for testosterone appeared in market. Today, over a hundred products including testosterone boosters–supplements that claim to naturally boost the body’s ability to produce testosterone–are available in market.

Testosterone levels by age

The average testosterone levels in men vary throughout their life span. They play a crucial role in the health and development of the human male from conception to well into the old age. Key changes in testosterone levels in the life cycle of males are:

In the seventh week of pregnancy, testosterone production starts in male embryo and the levels remain high until pregnancy for fetal development and normal differentiation of male infants

The levels drop before birth and remain comparable in male and female babies at pregnancy

Right after birth, the levels rise for the first 3 months in boys and then decrease and stay low for years until puberty

During puberty, the levels rise in order to develop secondary male characteristics, sexual behavior and function, as well as sperm production

By the age of 17, total testosterone levels in the blood plasma rise to levels of 300 – 1000 ng/dL (or 10 – 35 nmol/L) based on data collected by Griffin and Wilson (2001) and Merck (2003)

The bioavailable testosterone levels in men remain that high until their 30s and 40s, then drop at a rate of about 1.2% per year as shown by data from Griffin and Wilson (2001) and Harman (2001); the decrease in total testosterone is slower because the binding protein (SHBG) increase with age by approximately 0.4% per year

Data collected from various studies (plot at the top) show the testosterone levels keep dropping through out the life

Where is testosterone produced in the body?

The Leydig cells in testes produce most of testosterone in men. A small amount is also produced in the adrenal cortex (the surface of adrenal glands that releases other hormones including cortisol).

There are four key players in the production of testosterone as displayed in the graph below:

As a first step, hypothalamus in the brain releases GnRH (gonadotropin releasing hormone)

In men, the LH directs Leydig cells to produce testosterone; the FSH stimulates production of sperms in the Sertoli cells

Research suggests approximately 5-6 mg of testosterone is released daily into the blood stream of an adult male

LH and testosterone levels pulsate every 60-90 minutes; a closed loop maintains the diurnal rhythm starting with GnRH release by hypothalamus to final testosterone release into the blood stream

Several factors related to age affect the lower levels in older men:

A gradual decline of testosterone production in testes and GnRH production in the hypothalamus

Slow metabolism of the circulating testosterone in blood results in less production by the glands

The levels are also strongly influenced by body mass index (BMI = weight/height*height), waist to hip ratio, alcohol consumption, smoking, caffeine intake, and the time of sample collection. Several studies have consistently shown high BMI and abdominal mass related to lower testosterone in older men (www.nap.edu/10852).

However, the decline is gradual unlike the rapid decline of estrogen in women after menopause

Testosterone is produced through a complex biological cycle that involves five key steps–and multiple enzymatic reactions– to convert cholesterol into testosterone as the final product.

The plasma cholesterol first converts to pregnenolone followed by progesterone and DHEA, then androstenediol and androstenedione, and finally testosterone. The enzyme 5-alpha reductase converts some of the testosterone into DHT (dihydrotestosterone) in prostate, skin, and reproductive tissue. Rest of it is converted to estrogen in the fat cells and liver.

Therefore, in older men, an increase in fat cells might result in higher estrogen conversion.

What is total testosterone, free testosterone, and bioavailable testosterone?

Only about 2% of testosterone circulating in the blood is unbound, free testosterone. The rest is either weakly bound to albumin (60%) or tightly bound to SHBG (sex hormone binding globulin; approx. 40%). The weakly bound testosterone can rapidly dissociate whenever needed.

Therefore, together with free testosterone, approximately 42% testosterone is available for the tissues as bioavailable testosterone. Because SHBG is known to increase with age, the ratio of tightly bound testosterone increases in older men.

Testosterone levels follow a 24-hour diurnal rhythm, which is not as pronounced as seen in cortisol. Levels are highest around after 30 minutes of waking up, and then drop throughout the day. The circadian pattern appears less pronounced in older men (Bremmer 1983, Tenover 1998).

In general, levels can vary significantly from person to person and variables like age, alcohol, smoking, BMI, exercise need to be carefully considered when checking.

How to measure testosterone levels?

Testosterone can be measured using a blood or saliva sample. The traditional method using blood serum can measure total testosterone (protein bound plus free), free testosterone (not bound to protein), and bioavailable testosterone (albumin bound plus free). Different methods are used for measuring each of them:

Total testosterone measurement using radioimmunoassay is a widely used method. However, the binding protein SHBG (sex hormone binding globulin) increases with age. Therefore, in older patients a higher percentage of testosterone may be bound and not available to the tissues. That means this measurement might not be most useful for older population.

Bioavailable testosterone can be measured by first precipitating SHBG and then measuring the remaining testosterone in the serum. Or it can be calculated by subtracting the SHBG levels from total testosterone. Again, it has the drawback of inaccurate total testosterone in older population due to age dependence of SHBG levels.

Free testosterone can be calculated from measurement of total testosterone, SHBG, and albumin levels. It can also be directly measured by somewhat expensive equilibrium dialysis methods or immunoassays.

In last few decades, the saliva testing of testosterone has become a popular method. This immunoassay or ELISA based testosterone test has been standardized and validated with high reproducibility in recent years. The method has become popular due to multiple reasons:

Only unbound, free testosterone is able to diffuse through cells and the saliva test will measure this free testosterone.

Since this test measures the free testosterone, no interference from binding proteins is observed; as a direct measurement, it also doesn’t require any mathematical estimation for binding proteins and free testosterone.

The ability to collect multiple samples without requiring a health professional in the field should make it a superior choice in future testing

It is a non-invasive stress-free process–important consideration for children and those afraid of needles

Because testosterone levels fluctuate throughout the day, it allows the ability to collect multiple samples as necessary

A CLIA certified lab with well established references is recommended to test free testosterone. However, a general lack of awareness among physicians about the accuracy, reproducibility, and validity has made this method less popular. .

For diagnosis of hypogonadism, the following steps are recommended:

A low testosterone test as a first step (using sample collected in the morning)

A comprehensive history and physical exam if one believes they do not have normal testosterone levels

A second lab test from sample collected in the morning

The diagnosis can be tricky as low levels may be marker of ill health (not cause of it). There are still no clear guidelines of what levels are considered deficient and there is uncertainty regarding which measure of T should be used (total, free, or bioavailable)?

If data from few published studies were to be used as a general testing guideline then:

For those over 50, AACE (American Association of Clinical Endocrinologists), the guidelines (from 2002) recommend:

Total T between 200 and 400 ng/dL: further testing and consideration for therapy

Total T > 400 ng/dL: no deficiency

Other studies suggest deficiency in older men at 2-std dev from normal levels of testosterone in young men (Heaton, 2003):

Total T < 320 ng/dL

Free T < 7 ng/dL

Bioavailable T: 90 – 230 ng/dL

For our home testosterone test kits from saliva samples, we define a free testosterone value below 5 ng/dL (50 pg/mL on the report) as low and recommend further attention and changes in lifestyle.

Those below 1 ng/dL (10 ng/dL on the report) should immediately test again with a different sample and are recommended to talk to their primary physician.

FDA guidelines for testosterone prescription

The FDA explicitly recommends use of prescription only in certain medical conditions. Hypogonadism (unusually low testosterone levels) is a medical condition resulting from inadequate gonadal function, a deficiency in sperm production, and gonadal hormone secretion. Depending on the cause, it is classified into two types:

Primary hypogonadism: when testes do not function properly due to surgery, radiation, genetic and developmental disorders, infection, or liver and kidney diseases. In a genetic disorder, called Klinefelter’s syndrome—where an extra sex chromosome XXY is observed. Primary hypogonadism results in low testosterone, but high FSH and LH levels.

The FDA has recognized abuse of testosterone products and has provided guidelines for approval and prescription of testosterone products. In summary:

Only to be prescribed for men who have low levels of testosterone caused by certain medical conditions (e.g., problems with pituitary glands, hypothalamus in brain, damage to testicles)

FDA explicitly says that the ‘benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone’

Some studies have indicated increased cardiovascular risk associated with testosterone use, including aging men taking testosterone. Some studies reported an increased risk of heart attack, stroke, or death associated with low testosterone treatment, while others did not

The diagnosis of clinically low testosterone, or hypogonadism, requires two separate lab tests as evidence (and samples collected in the morning)

Testosterone is a Schedule III controlled drug due to abuse potential; each refill may need to have a new prescription

Based on available data, the FDA says those taking therapy are at higher risk of stroke and heart attack like symptoms and should monitor them carefully:

Chest pain

Shortness of breath and trouble breathing

Weakness in one part or one side of body

Slurred speech

Testosterone and Aging in US population

Data from US Census Bureau projects the ratio of older population will keep increasing in foreseeable future. The plot below shows US population projections for 2018 and 2030.

In the highlighted region the population of 30 years and older is projected to be 15% more in 2030. That’s approximately 15 million more men with declining testosterone levels and searching for answers regarding their health outcomes. That is a strong motivation for scientists, researchers, and medical providers to find better answers.

For those serving this market segment, the opportunities are enormous.

Read the Wired Magazine’s perspective on T: https://www.wired.com/story/testosterone-treatment-myth/ (15 minute ready going through brief history, how middle aged men are going after testosterone theory, and how the industry is trying to advertise the benefits although scientific data are scarce)

Testosterone and Aging: Clinical Research Directions (2003) www.nap.edu/10852 (studies reviewed by a committee of experts in the field assembled by the Institute of Medicine of the National Academies)

Drugwatch.com’s superb review of testosterone therapy: https://www.drugwatch.com/testosterone/ (an comprehensive and authoritative review on the background and scientific literature of testosterone, a must read for those interested to know more)

Disclaimer: For information purposes only, not to be used for diagnosis or replace advice from a medical professional. An at home testosterone test can be ordered here. Information on other health tests can be found here. You can order a CLIA-certified at-home health test from www.RxHomeTest.com anytime for free shipping and physician approved reports.